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1.
Clin Genet ; 88(6): 531, 2015 Dec.
Article in English | MEDLINE | ID: mdl-26507258

ABSTRACT

A point mutation in PDGFRB causes autosomal-dominant Penttinen syndrome Johnston JJ et al. (2015) American Journal of Human Genetics 97(3): 465-474.


Subject(s)
Acro-Osteolysis/genetics , Acro-Osteolysis/pathology , Limb Deformities, Congenital/genetics , Limb Deformities, Congenital/pathology , Point Mutation/genetics , Progeria/genetics , Progeria/pathology , Receptor, Platelet-Derived Growth Factor beta/genetics , Signal Transduction/genetics , Female , Humans , Male
4.
Pharmacogenomics J ; 14(6): 555-63, 2014 Dec.
Article in English | MEDLINE | ID: mdl-24861855

ABSTRACT

Differences in the frequency of pharmacogenomic variants may influence inter-population variability in drug efficacy and risk of adverse drug reactions (ADRs). We investigated the diversity of ∼ 4500 genetic variants in key drug-biotransformation and -response genes among three South East Asian populations compared with individuals of European ancestry. We compared rates of reported ADRs in these Asian populations to determine if the allelic differentiation corresponded to an excess of the associated ADR. We identified an excess of ADRs related to clopidogrel in Singaporean Chinese, consistent with a higher frequency of a known risk variant in CYP2C19 in that population. We also observed an excess of ADRs related to platinum compounds in Singaporean CHS, despite a very low frequency of known ADR risk variants, suggesting the presence of additional genetic and non-genetic risk factors. Our results point to substantial diversity at specific pharmacogenomic loci that may contribute to inter-population variability in drug response phenotypes.


Subject(s)
Drug-Related Side Effects and Adverse Reactions , Genetic Variation/genetics , Biotransformation , Europe , Humans , Singapore
5.
Clin Genet ; 86(1): 21-8, 2014 Jul.
Article in English | MEDLINE | ID: mdl-24684508

ABSTRACT

The vast range of genetic diversity contributes to a wonderful array of human traits and characteristics. Unfortunately, a consequence of this genetic diversity is large variability in drug response between people, meaning that no single medication is safe and effective in everyone. The debilitating and sometimes deadly consequences of adverse drug reactions (ADRs) are a major and unmet problem of modern medicine. Pharmacogenomics can uncover associations between genetic variation and drug safety and has the potential to predict ADRs in individual patients. Here we review pharmacogenomic successes leading to changes in clinical practice, as well as clinical areas probably to be impacted by pharmacogenomics in the near future. We also discuss some of the challenges, and potential solutions, that remain for the implementation of pharmacogenomic testing into clinical practice for the significant improvement of drug safety.


Subject(s)
Biomarkers, Pharmacological , Genetic Testing/methods , Genetic Variation , Pharmacogenetics/methods , Pharmacogenetics/trends , Precision Medicine/methods , Anthracyclines/pharmacology , Carbamazepine/pharmacology , Cisplatin/pharmacology , Codeine/pharmacology , Humans , Precision Medicine/trends , Warfarin/pharmacology
8.
Pharmacogenomics J ; 14(2): 160-70, 2014 Apr.
Article in English | MEDLINE | ID: mdl-23588107

ABSTRACT

There is established clinical evidence for differences in drug response, cure rates and survival outcomes between different ethnic populations, but the causes are poorly understood. Differences in frequencies of functional genetic variants in key drug response and metabolism genes may significantly influence drug response differences in different populations. To assess this, we genotyped 1330 individuals of African (n=372) and European (n=958) descent for 4535 single-nucleotide polymorphisms in 350 key drug absorption, distribution, metabolism, elimination and toxicity genes. Important and remarkable differences in the distribution of genetic variants were observed between Africans and Europeans and among the African populations. These could translate into significant differences in drug efficacy and safety profiles, and also in the required dose to achieve the desired therapeutic effect in different populations. Our data points to the need for population-specific genetic variation in personalizing medicine and care.


Subject(s)
Acquired Immunodeficiency Syndrome/genetics , Drug-Related Side Effects and Adverse Reactions/genetics , Neoplasms/genetics , Tuberculosis/genetics , Acquired Immunodeficiency Syndrome/drug therapy , Acquired Immunodeficiency Syndrome/pathology , Black People/genetics , Drug-Related Side Effects and Adverse Reactions/pathology , Gene Frequency , Genetic Predisposition to Disease , Genetic Variation , Humans , Neoplasms/drug therapy , Neoplasms/pathology , Polymorphism, Single Nucleotide , Tuberculosis/drug therapy , Tuberculosis/pathology , White People/genetics
12.
Clin Genet ; 83(1): 32-3, 2013 Jan.
Article in English | MEDLINE | ID: mdl-23043298
13.
Tissue Antigens ; 73(6): 599-603, 2009 Jun.
Article in English | MEDLINE | ID: mdl-19392800

ABSTRACT

Killer cell immunoglobulin-like receptors (KIRs) on chromosome 19q13.4 regulate the function of not only human natural killer (NK) cells but also T cells. An increase in activating KIR- human leucocyte antigen ligand pairs has been associated with an additional risk to develop type 1 diabetes (T1D). T1D families [n = 184 (552 individuals); n = 176 (528 subjects)], unrelated T1D patients (n = 380; n = 394) and healthy controls (n = 315; n = 401) from Germany and Belgium, respectively, were genotyped for the rs2756923 polymorphism within the KIR gene cluster haplotype B in exon 8 of the KIR2DL2 gene. We observed in both Germans and Belgians an overtransmission of the allele 'G' of the KIR2DL2-rs2756923 polymorphism (64.2% vs 35.8%, P = 3 x 10(-4) and 60.0% vs 40.0%, P = 0.02, respectively). In addition, this allele was more frequent in German patients than in healthy controls (78.4% vs 21.6%, P = 1 x 10(-3)). Preliminary results from a cytotoxicity assay suggest that inhibition of NK-cell cytotoxicity may be impaired in individuals carrying the rs2756923 G allele. These data suggest a potential role of the KIR2DL2-rs2756923 polymorphism in T1D in Germans and Belgians.


Subject(s)
Diabetes Mellitus, Type 1/genetics , Gene Frequency/genetics , HLA-C Antigens/genetics , Killer Cells, Natural/metabolism , Receptors, KIR2DL2/genetics , Alleles , Belgium , Cell Line, Tumor , Cytotoxicity, Immunologic/genetics , Cytotoxicity, Immunologic/immunology , Female , Genetic Predisposition to Disease , Genotype , Germany , HLA-C Antigens/metabolism , Haplotypes/genetics , Humans , Killer Cells, Natural/immunology , Male , Polymorphism, Single Nucleotide/genetics , Receptors, KIR2DL2/immunology
14.
Tissue Antigens ; 68(2): 147-52, 2006 Aug.
Article in English | MEDLINE | ID: mdl-16866884

ABSTRACT

Type 1 diabetes is an autoimmune heterogeneous disease that is determined by environmental and genetic factors. A possible retroviral etiology has been inferred from the observation that human endogenous retrovirus (HERV)-K18 encoding a superantigen (SAg) has a polymorphism associated with this disease. Type 1 diabetes families from Germany and Belgium were genotyped for the novel HERV-8914 (303 families) and for the known HERV-8594 (284 families) polymorphisms within the SAg-coding region on the HERV-K18. Case-control analysis was performed for the HERV-8914 polymorphism (506 patients) and for the HERV-8594 polymorphism (370 patients) and compared with 350 German controls. Haplotypes were constructed. Additionally, a microsatellite within the CD48 gene was analyzed in German type 1 diabetes families (n=125) as well as in patients (n=375) and in healthy controls (n=350). No association was found for HERV-K18 polymorphisms or the CA repeat within the CD48 gene with type 1 diabetes mellitus either in families or by comparing patients and controls. In conclusion, we cannot confirm a role of HERV-K18 polymorphisms -HERV-8914 and HERV-8594- or of the CD48 CA repeat for type 1 diabetes susceptibility.


Subject(s)
Antigens, CD/genetics , Diabetes Mellitus, Type 1/genetics , Endogenous Retroviruses/genetics , Membrane Proteins/genetics , Superantigens/genetics , CD48 Antigen , Case-Control Studies , Child , Child, Preschool , Dinucleotide Repeats , Female , Genetic Predisposition to Disease , Genotype , Humans , Introns/genetics , Linkage Disequilibrium , Male , Polymorphism, Genetic , Software
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